APPLICANT'S DESCRIPTION: (provided by Applicant) Penclomedine (PEN), 2-trichloromethyl-3, 5-dichloro-4, 6-dimethoxypyridine, a novel agent evaluated in Phase I clinical trials, caused dose limiting neurotoxicity and was withdrawn from further development. Collaborative studies by investigators from Johns Hopkins University Oncology Center, the FDA and Southern Research Institute identified the major plasma metabolite in patients as 4-demethyl-PEN (4-DM-PEN), an antitumor active, non-neurotoxic agent. Further studies by the applicant led to synthesis of 4-acyl derivatives, which were superior to 4-DM-PEN in their anticancer activity against MX-1 human breast tumor xenografts in vivo implanted sc or intracranially (ic). In order to optimize the antitumor activity of 4-DM-PEN, synthesis of a series of acyl, carbonate, thiolocarbonate, carbamate, thiocarbamate, phosphate, phosphonate, phosphinate, sulfate, sulfonate, sulfinate and (-glucuronide derivatives is proposed for evaluation initially vs. orthotopically implanted MX-1 and U251 CNS human tumor xenografts and subsequently vs. other tumor types, including DNA mismatch repair proficient and deficient human glioma xenografts, with the goal of selecting the best candidate for a Phase I/II clinical trial vs. brain tumors, funded by an awarded NCI/NIH SBIR grant to a collaborator. Pharmacology studies are proposed to identify whether the major plasma metabolite is 4-DM-PEN or the 4-substituted derivatives, and tumor DNA binding investigations are proposed to determine if the major binding form is derived via free-radical activation in the liver from 4-DM-PEN or the derivatives, as an indication of the likely mechanism of action. Finally, DNA cross linking studies, which have demonstrated a preference for G-X-C sequences, will be expanded in an attempt to identify whether the crosslink occurs between the liver-generated dichloromethene moiety and the 3- or 5-site on the pyridine ring.